Background: Active surveillance for transmissible spongiformencephalopathies in smallruminants has been an EU regulatory requirement since 2002. A number ofEuropean countrieshave subsequently reported cases of atypical scrapie, similar to previouslypublished cases fromNorway, which have pathological and molecular features distinct fromclassical scrapie. Most caseshave occurred singly in flocks, associated with genotypes considered to bemore resistant toclassical disease. Experimental transmissibility of such isolates has beenreported in certain ovinisedtransgenic mice, but has not previously been reported in the natural host.Information on thetransmissibility of this agent is vital to ensuring that disease controlmeasures are effective andproportionate.

Results: This report presents the successful experimental transmission, in378 days, of atypicalscrapie to a recipient sheep of homologous genotype with preservation of thepathological andmolecular characteristics of the donor. This isolate also transmitted toovinised transgenic mice(Tg338) with a murine phenotype indistinguishable from that of Nor 98.Conclusion: This result strengthens the opinion that these cases result froma distinct strain ofscrapie agent, which is potentially transmissible in the natural host underfield conditions.

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DiscussionTo our knowledge this is the first report of the successfulexperimental transmission of atypical scrapie within thenatural host. The retention of the molecular and pathologicalcharacteristics of the scrapie agent following thisexperimental transmission supports the hypothesis thatdisease in the donor animal was caused by a stable strainof the TSE agent which has phenotypic characteristics distinctfrom those associated with classical scrapie.Although clinical signs were not recorded from the donoranimal because it presented dead (fallen stock), the signsseen in the challenged animal were consistent with thosereported for the small number of passive surveillancecases so far identified in the UK [14,15] and elsewhere[6,16], which were characterised by gait abnormalities,abnormal behaviour and a relative lack of pruritic signs.The transmission characteristics of atypical scrapie fromdifferent countries in Tg338 mice [12] and emerging datafrom similar transmissions of the isolate in this reportindicate that at least one strain of atypical scrapie compatiblewith/indistinguishable from Nor98 is widespreadacross Europe, despite its relatively recent identification.Although it has now been demonstrated to be experimentallytransmissible within and between species via theintracerebral route, there is little epidemiological evidencefor ease of transmission of this strain under field conditions,where scrapie is most likely transmitted via the oralroute. This raises the question of how it came to be so geographicallywidespread. One hypothesis is that this repre-sents a spontaneous genetic disease in sheep similar to thefamilial forms of TSE in man (e.g. GSS, familial CJD andFFI etc.), in which the resultant disease can subsequentlybe transmitted experimentally [17,18].Horizontal transmission of classical scrapie has beenshown to occur in adult sheep exposed to an affected flock[19] and even in animals which have had contact onlywith a contaminated environment (GI Dexter and SJ Bellworthy,personal communication). The environmentalpersistence of the classical scrapie agent is also supportedby epidemiological evidence from Icelandic repopulationstudies [20,21]. However, the low molecular mass (<14kD) band of PrPSc seen in Western blots of atypical isolatesis associated with a reduction in PK resistance of this disease-associated protein. It is possible that this relative proteasesusceptibility may make the agent less robust in fieldconditions and thereby reduce the extent to which it istransmissible by natural routes, and so limit the numberof cases. It could be argued that this in turn supports thehypothesis that the natural disease may arise spontaneously.However, although genetic studies have indicated aPrP genotype host range for atypical scrapie which, for themajority of cases, is almost fully distinct from that of theclassical forms of disease, they have not identified a singlegenetic feature (such as the point mutations in somehuman forms [22]) which might account for this.This relative PrPSc fragility [23] compared to the PrPSc inclassical scrapie, may also account for the total absence ofintracellular PrPSc immunolabelling. The different PKcleavage sites in PrP associated with different strains ofTSE infecting small ruminants can be used to differentiatethem, both in blots and by immunohistochemistry. Intracellularimmunostaining is significantly reduced in sheepinfected with BSE compared to classical scrapie, when theappropriate monoclonal antibodies are applied, and ithas been speculated that this demonstrates a partial digestionof the PrPSc molecule by the endogenous proteaseswithin the cells [24]. If the PrPSc is more protease sensitive,then this loss of intracellular immunolabelling even withan antibody to the core of the protein (such as MAb2G11) might indicate that cells can more effectivelycatabolise this abnormal form of the protein than more'classical' forms, and therefore succumb to clinical diseasemuch later, if at all. This may also account for the apparentabsence of disease-related PrPSc in lymphoid tissues. Itis interesting to note that in familial CJD (E200K mutation)also, PrP labelling was seen as a uniformly finedeposit throughout all cortical layers [25].This study confirms that 'atypical scrapie' is transmissiblewithin the natural host species, via the intracerebral route,without alteration of the pathological and molecular characteristics.This is the first report from a larger study whichwill explore more widely the effect of the PrP gene on theexperimental susceptibility and resultant phenotype followingintracerebral or oral challenge with this type ofscrapie isolate.

Conclusion

At present the significance of this result, in terms of thetransmissibility or pathogenicity under 'field conditions'of this agent strain in any species remains speculative, butit supports the need for appropriate control measures protectingboth the animal and the human food chain toencompass atypical scrapie cases specifically.

http://www.biomedcentral.com/content/pdf/1746-6148-3-20.pdf

WHY not the potential for some of the cases of atypical scrapie being aresult of a food born exposure asevidence pointed out for the typical scrapie ???

EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE

This is provided by the statistically significant increase in the incidenceof sheep scrape from 1985, as determined from analyses of the submissionsmade to VI Centres, and from individual case and flock incident studies.........

To minimise the risk of farmers' claims for compensation from feedcompounders.

To minimise the potential damage to compound feed markets through adversepublicity.

To maximise freedom of action for feed compounders, notably bymaintaining the availability of meat and bone meal as a rawmaterial in animal feeds, and ensuring time is available to make anychanges which may be required.

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THE FUTURE

4..........

MAFF remains under pressure in Brussels and is not skilled athandling potentially explosive issues.

5. Tests _may_ show that ruminant feeds have been sold whichcontain illegal traces of ruminant protein. More likely, a few positivetest results will turn up but proof that a particular feed mill knowinglysupplied it to a particular farm will be difficult if not impossible.

6. The threat remains real and it will be some years before feedcompounders are free of it. The longer we can avoid any directlinkage between feed milling _practices_ and actual BSE cases,the more likely it is that serious damage can be avoided. ...

Nor98 is a prion disease of old sheep and goats. This atypical form ofscrapie was firstdescribed in Norway in 1998. Several features of Nor98 were shown to bedifferentfrom classical scrapie including the distribution of disease associatedprion protein(PrPd) accumulation in the brain. The cerebellum is generally the mostaffected brainarea in Nor98. The study here presented aimed at adding information on theneuropathology in the cerebellum of Nor98 naturally affected sheep ofvariousgenotypes in Sweden and Norway. A panel of histochemical andimmunohistochemical(IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidicprotein,amyloid, and cell markers for phagocytic cells were conducted. The type ofhistologicallesions and tissue reactions were evaluated. The types of PrPd depositionwerecharacterized. The cerebellar cortex was regularly affected, even thoughthere was avariation in the severity of the lesions from case to case. Neuropilvacuolation wasmore marked in the molecular layer, but affected also the granular celllayer. There wasa loss of granule cells. Punctate deposition of PrPd was characteristic. Itwasmorphologically and in distribution identical with that of synaptophysin,suggestingthat PrPd accumulates in the synaptic structures. PrPd was also observed inthegranule cell layer and in the white matter. ***The pathology features ofNor98 in thecerebellum of the affected sheep showed similarities with those of sporadicCreutzfeldt-Jakob disease in humans.